James Heyes

RNAi-mediated gene silencing in non-human primates.

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg-1. A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.

Antitumour evaluation of a ribonuclease resistant double-stranded RNA-polyquaternary ammonium complex (BRL 10739)

Abstract A double-stranded RNA (BRL 5907 ) isolated from a mycophage and one of its soluble polyquaternary ammonium complexes (BRL 10739 ) have been shown to have good activity against the well established solid L 5178 Y lymphoma. Good antitumour activity is also seen against the Lewis lung carcinoma on both the primary and the ensuing pulmonary metastases. In these two systems the complex BRL 10739 consistently showed superior activity to the parent nucleic acid. Excellent resistance to breakdown by pancreatic ribonuclease and by human serum was shown by the complex in direct contrast to the natural ds-RNA. The complex was shown to be more toxic in the mouse when compared with the parent material.